WO2012012809A2 - Application de chlores-dihydroxy β-fonctionnalisés pour tpd - Google Patents

Application de chlores-dihydroxy β-fonctionnalisés pour tpd Download PDF

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WO2012012809A2
WO2012012809A2 PCT/US2011/047576 US2011047576W WO2012012809A2 WO 2012012809 A2 WO2012012809 A2 WO 2012012809A2 US 2011047576 W US2011047576 W US 2011047576W WO 2012012809 A2 WO2012012809 A2 WO 2012012809A2
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Prior art keywords
group
substituent
substituted
phenyl ring
carbon atoms
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PCT/US2011/047576
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WO2012012809A3 (fr
Inventor
Daniel Aicher
Arno Wiehe
Christian B. W. Stark
Volker Albrecht
Susanna Grafe
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Ceramoptec Gmbh
Ceramoptec Industries, Inc.
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Priority to PL11810524T priority Critical patent/PL2870159T3/pl
Priority to EP11810524.6A priority patent/EP2870159B1/fr
Priority to MX2013000877A priority patent/MX353394B/es
Priority to PCT/US2011/047576 priority patent/WO2012012809A2/fr
Priority to JP2013520904A priority patent/JP2013532664A/ja
Priority to BR112013001576A priority patent/BR112013001576A2/pt
Priority to CN201180039522.7A priority patent/CN103097390B/zh
Publication of WO2012012809A2 publication Critical patent/WO2012012809A2/fr
Publication of WO2012012809A3 publication Critical patent/WO2012012809A3/fr
Priority to IL224381A priority patent/IL224381B/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings

Definitions

  • the invention relates to the chemistry of biologically active compounds. More particularly to ⁇ functionalized chlorin derivatives that can be used as
  • photosensitizers for a wide range of light irradiation treatments such as photodynamic therapy of cancer, infections and other diseases.
  • Photodynamic therapy is one of the most promising new techniques now being explored for use in a variety of medical applications and particularly is a well-recognized treatment for the destruction of tumors.
  • Photodynamic therapy uses light and a photosensitizer (a dye) to achieve its desired medical effect.
  • a large number of naturally occurring and synthetic dyes have been evaluated as potential photosensitizers for photodynamic therapy.
  • Perhaps the most widely studied class of photosensitizers are tetrapyrrolic macrocyclic compounds. Among them, especially porphyrins and chlorins have been tested for their PDT efficacy.
  • Porphyrins are macrocyclic compounds with bridges of one carbon atom joining pyrroles to form a
  • Patent Publication N° US 04656186 by Bommer et al. discloses fluorescent mono, di- or polyamide of an aminocarboxylic acid and tetrapyrrole containing at least three carboxyl groups. Patent N° US 04656186 by Bommer et al.
  • Chlorins possessing potential for PDT can either be derived from natural sources or from total synthesis.
  • chlorins are derived from natural compounds they are usually obtained by derivatizing chlorophylls or bacteriochlorophylls, as for example the
  • chlorins possesses a diketo-group in one of the four pyrrolic subunits.
  • these diketo-chlorins are not suitable for application in PDT e.g. due to their very weak absorption in the red region.
  • Some different ways can be found in the art to synthesize these kinds of chlorins.
  • a possible way is the direct oxidation of dihydroxychlorins obtained by dihydroxylation for example with 2,3-dichloro-5,6- dicyano-benzoquinone as oxidizing agent (H. W. Daniell, S. C. Williams, H. A.
  • photo sensitizers capable of efficiently destroying deep target tissues by intensively absorbing light in the red and near-infrared region of the electromagnetic spectrum.
  • formulations for the biologically active compounds of the present invention such as a liposomal formulation to be injected avoiding undesirable effects like precipitation at the injection site or delayed pharmacokinetics of the tetrapyrrole systems.
  • the present invention provides methods to obtain biologically active compounds that can be used as photo sensitizers for diagnostic and therapeutic applications, particularly for PDT of cancer, infections and other hyperproliferative diseases, fluorescence diagnosis and PDT treatment of a non-tumorous indication such as arthritis, inflammatory diseases, viral or bacterial infections, dermatological, ophthalmological or urological disorders.
  • An embodiment of the present invention consists of a method to synthesize hydroxy- or dihydroxy-chlorins, which possess additional substituents in the oxidized J-pyrrolic subunit by transformation of diketo- chlorins with nucleophilic or organometallic agents.
  • Another object of the present invention is to provide amphiphilic compounds with a higher membrane affinity and increased PDT-efficacy.
  • Another embodiment of the present invention consists of formulating the desired isomer into a liposomal formulation to be injected avoiding undesirable effects like precipitation at the injection site or delayed pharmacokinetics of the tetrapyrrole systems.
  • Figure 1.- shows the general formula of the embodiments of the tetrapyrrolic compounds of present invention.
  • Figure 2. shows chemical formulas 1 and 2 which are the basis for embodiments of the tetrapyrrolic compounds of present invention.
  • Figure 3. shows chemical formula 3, which is the basis for embodiments of the tetrapyrrolic compounds of present invention.
  • Figure 4.- shows chemical formula 4, which is the basis for embodiments of the tetrapyrrolic compounds of present invention.
  • Figure 5.- shows chemical formula 5, which is the basis for embodiments of the tetrapyrrolic compounds of present invention.
  • Figure 6. shows an embodiment of a tetrapyrrolic compound of present invention based on chemical formula 3.
  • Figure 7.- shows another embodiment of a tetrapyrrolic compound of present invention based on chemical formula 3
  • Figure 8.- shows another embodiment of a tetrapyrrolic compound of present invention based on chemical formula 3.
  • Figure 9. shows an embodiment of photodynamic activity of 5,10,15,20- tetrakis-(3-hydroxyphenyl)-7 ; 8-bis-(trifluoromethyl)-7,8-dihydroxy-7,8-cWorin against HT29 cell line.
  • Figure 10. shows an embodiment of photodynamic activity of 5,10,15,20- tetrakis-(3-hydroxyphenyI)-7,8-dihexy]-7 ! 8-dihydroxy-7,8-chlorin against HT29 cell line.
  • Figure 11. shows an embodiment of photodynamic activity of 5,10,15,20- tetraki s-(3 -hydroxypheny l)-7, 8 -bis- [3 , 5 -bis-(trifluoromethyl) -phenyl]-7 , 8 -dihydroxy- 7,8-chlorin against HT29 cell line.
  • Figure 12. shows an embodiment of photodynamic activity of 5,10,15,20- tetrakis-(3-hydroxyphenyl)-7,8-bis-(trifluoromethyl)-7,8-dihydroxy-7,8-chlorin against synoviocytes and macrophages.
  • Figure 13.- shows an embodiment of photodynamic activity of 5,10,15,20- tetrakis-(3-hydroxyphenyl)-7,8-dihexyl-7,8-dihydroxy-7,8-chJorin against synoviocytes and macrophages.
  • Figure 14.- shows an embodiment of photodynamic activity of 5, 10,15,20- tetrakis-(3-hydroxyphenyl)-7,8 ⁇ bis-[3,5-bis-(trifluoromethyl)-phenyl]-7,8-dihydroxy- 7,8-chlorin against synoviocytes and macrophages.
  • the present invention provides biologically active compounds that can be used as photosensitizers for a wide range of light irradiation treatments such as
  • the alternative photosensitizers provided by the present invention have the advantage that they are easily produced and characterized.
  • the present invention allows the further functionalization of effective photosensitizers to enhance their activity, stability or make new applications possible.
  • the present invention provides methods to tailor amphiphilic compounds for desired PDT applications, target tissue selectivity is increased and thus PDT efficacy.
  • the present invention enhances the effectiveness of prior art biologically active compounds offering a deeper tissue penetration due to their strong absorption at long wavelength of the red and near-infrared region of the electromagnetic spectrum, enhanced selectivity for target tissues over healthy surrounding tissues due to its tailored amphiphilicity and custom-made pharmacokinetic behavior depending on the particular PDT application.
  • the biologically active compounds of the present invention that can be used for different medical indications, particularly PDT, are meso-substituted and ⁇ - functionalized hydroxy- or dihydroxy-chlorin structures. Additionally, the invention extends their applications as the structures can be employed for fluorescence diagnosis and PDT treatment of non-tumorous indications such as arthritis and similar inflammatory diseases.
  • a tetrapyrrolic compound has the general formula depicted in figure 1.
  • a tetrapyrrolic compound is based on the formulas 1 or 2 depicted in figure 2, wherein R l , R 2 , R 3 or R 4 are independently a hydrogen, a substituted or unsubstituted alkyl, or fiuoroalkyl group consisting of 1-15 carbon atoms, a substituted or unsubstituted aromatic ring; and R 5 is a substituted or unsubstituted alkyl, aikenyl, alkinyl or fiuoroalkyl group consisting of 1-15 carbon atoms or a substituted or unsubstituted aromatic ring.
  • a tetrapyrrolic compound is based on the formulas 1 or 2 depicted in figure 2; and R 1 , R 2 , R 3 or R 4 are independently a hydrogen, a substituted or a unsubstituted alkyl, or a fiuoroalkyl group consisting of 1-15 carbon atoms, a phenyl ring or a phenyl ring with one or more substituents X either in the ortho-, meta- or /wra-position.
  • Substituent X is preferably OH, -COOH, -N3 ⁇ 4, -CF 3, - F, -COOY, -NHY, -OY, -NH-Z-COOH, or -CO-Z-NH 2 ;
  • substituent Y is a
  • R 5 is a substituted or unsubstituted alkyl, aikenyl, alkinyl or fiuoroalkyl group consisting of 1-15 carbon atoms, a phenyl ring or a phenyl ring with one or more substituents X either in the ortho-, meta- or ⁇ ara-position.
  • substituent X is OH, -COOH, -N3 ⁇ 4, -CF 3, -F, -COOY, -NHY, - OY, -NH-Z-COOH, or -CO-Z-NH 2 ;
  • substituent Z are peptides or oligopeptides.
  • R 5 is a substituted or unsubstituted alkyl, alkenyl, alkinyi or fluoroalkyl group consisting of 1-15 carbon atoms or a phenyl ring substituted with one or more CF 3 -groups either in the ortho-, meta- or para-position.
  • a tetrapyrrolic compound is based on the formulas 1 or 2, described in figure 2, wherein R 1 , R 2 , R 3 or R 4 are independently a substituted or unsubstituted alkyl or fluoroalkyl group consisting of 4-15 carbon atoms or a phenyl ring with one or more substituents X either in the meta- or para-position, and substituent X is OH, -COOH, -N3 ⁇ 4.
  • R 5 is a substituted or
  • alkyl unsubstituted alkyl, alkenyl, alkinyi or fluoroalkyl group consisting of 1-15 carbon atoms or a phenyl ring substituted with one or more CF 3 -groups either in the ortho-, meta- or para-position.
  • a tetrapyrrolic compound is based on the formula 3, as described in figure 3, wherein R is a substituted or unsubstituted alkyl, alkenyl, alkinyi or fluoroalkyl group consisting of 1-15 carbon atoms or a phenyl ring substituted with one or more CF 3 -groups either in the ortho-, meta- or para-position.
  • a tetrapyrrolic compound is based on the formula 4, depicted in figure 4, wherein R is a substituted or unsubstituted alkyl, alkenyl, alkinyi or fluoroalkyl group consisting of 1-15 carbon atoms or a phenyl ring substituted with one or more CF 3 -groups either in the ortho-, meta- or para-position.
  • a tetrapyrroHc compound is based on the formula 5, as described in figure 5, wherein Ris a substituted or unsubstituted alkyl, alkenyl, alkinyl or fluoroalkyl group consisting of 1-15 carbon atoms or a phenyl ring substituted with one or more CF 3 -groups either in the ortho-, meta- or para-position.
  • Ris a substituted or unsubstituted alkyl, alkenyl, alkinyl or fluoroalkyl group consisting of 1-15 carbon atoms or a phenyl ring substituted with one or more CF 3 -groups either in the ortho-, meta- or para-position.
  • a tetrapyrroHc compound is based on the formula 3, wherein R is a -CF 3 or a pharmaceutically acceptable derivative thereof.
  • a tetrapyrroHc compound is based on the formula 3, wherein R is a hex
  • a tetrapyrroHc compound is based on the formula 3 or a pharmaceutically acceptable derivative thereof.
  • the tetrapyrroHc compounds of all previous embodiments based on formulas 1, 2, 3, 4 and 5, or a pharmaceutically acceptable derivative thereof are used for the preparation of pharmaceutical compositions for diagnosis and photodynamic therapy.
  • a pharmaceutical composition comprises a
  • tetrapyrroHc compound according to previous embodiments, or a pharmaceutically acceptable derivative thereof, as an active ingredient.
  • the pharmaceutical composition in which any of the tetrapyrroHc compounds of previous embodiments is an active ingredient is a liposomal formulation.
  • a pharmaceutical composition in which a tetrapyrroHc compound according to all previous embodiments, or a pharmaceutically acceptable derivative thereof, is conjugated to a targeting agent.
  • the targeting agent of the pharmaceutical composition is an antibody, a fragment of an antibody, a peptide.
  • This pharmaceutical composition is preferably a liposomal formulation.
  • the tetrapyrrolic compounds of all previous embodiments based on formulas 1, 2, 3, 4 and 5, or a pharmaceutically acceptable derivative thereof are used in photodynamic therapy of tumors, dermatological disorders, viral or bacterial infections, ophthalmological disorders or urological disorders, arthritis and similar inflammatory diseases. Additionally, the mentioned compounds or pharmaceutically acceptable derivative thereof can be used in the diagnosis of arthritis and similar inflammatory diseases.
  • the tetrapyrrolic compounds depicted in previous embodiments are used in different therapeutic formulations according to the way of administration, comprising known carriers such as conventional liposomes, pegylated liposomes, nanoemulsions, nanocrystrals, nanoparticles, fatty emulsions, lipidic formulations, self-micro-emulsify ing-drug-deli very- systems, AIpha-Feto protein (AFP), Bovine-Seram-Albumin (BSA), poly(lactic-co-glycolic acid) (PLGA), fatty emulsions and organic or non-organic nanoparticles.
  • known carriers such as conventional liposomes, pegylated liposomes, nanoemulsions, nanocrystrals, nanoparticles, fatty emulsions, lipidic formulations, self-micro-emulsify ing-drug-deli very- systems, AIpha-Feto protein (AFP), Bovine-Seram-Album
  • the present invention uses chemically stable porphyrin derivatives and provides methods for preparation of the corresponding precursor diketo-chlorins.
  • An embodiment of the present invention consists of a method to synthesize hydroxy- or dihydroxy-chlorins from diketo-chlorins as precursors using nucleophilic agents like (trifluoromethyl)trimethylsilane or Grignard reagents e.g.
  • Another embodiment of the present invention consists of the steps of synthesizing a porphyrin with a defined arrangement of substituents, converting it to the diketo-chlorin and after that to the corresponding hydroxy- or dihydroxy-chlorins and then to formulate the desired compound into a liposomal formulation.
  • an Artype porphyrin with OT-methoxyphenyl substituents is synthesized and converted to the precursor diketo- chlorin which is converted to the corresponding ⁇ functionalized dihydroxy-chlorin. Then, the remaining methoxy groups are deprotected with BBr 3 to obtain the hydroxyl substituted derivative.
  • a porphyrin of the ' trans '-A 2 B 2 -type is synthesized, having hexyl chains as substituent A and methoxycarbonyl phenyl residues as substituent B.
  • This porphyrin is converted to the dihydroxychlorin and after that to the diketo-chlorin. Then, the precursor is converted to the / ⁇ functionalized dihydroxy-chlorin and the remaining methyl esters are hydrolyzed to receive the corresponding carboxylic acids.
  • Acceptable starting materials for the synthesis of the porphyrins which are the subject of the present invention are pyrrole and aldehydes. They are subjected to a condensation reaction. Suitable methods for this condensation have long been known in the art (J. S. Lindsey, I. C. Schreiman, H. C. Hsu, P. C. Kearney and A. M.
  • the unsymmetrically substituted porphyrins can also be synthesized using dipyrrom ethanes and aldehydes, as is also known in the art (C.-H. Lee, J. S. Lindsey, One-Flask Synthesis of Meso- Substituted Dipyrromethanes and Their Application in the Synthesis of Trans- Substituted Porphyrin Building Blocks, Tetrahedron 1994, 50, 11427-11440). After condensation and purification of the desired porphyrins these are converted to the diketo-chlorins by two different methods.
  • the first method is exemplified with examples 1.1, 1.3 and 1.5 and proceeds over 3 steps.
  • the first step is an osmiu tetroxide mediated dihydroxylation as it is known in the art.
  • the second step is the quantitative dehydration of the diol to form the corresponding 2-hydroxyporphyrin in refluxing trifluoroacetic acid.
  • another embodiment of the present invention provides a simple method for the dehydration of the dihydroxychlorins.
  • the Dess-Martin periodinane mediated oxidation of the 2- hydroxyporphyrin to the diketo-chlorin is the last step of the synthesis.
  • the second method is also known in the art and exemplified with examples 1.2 and 1.4. It is an alternative route to obtain 2-hydroxypo ⁇ hyrins avoiding the use of osmium tetroxide.
  • the porphyrin is converted to the corresponding Cu (II) mtro-porphyrin derivative using Cu(N0 3 ) 2 and in the second step the 2- hydroxyporphyrin is obtained by treating the nitro substituted porphyrin derivative with the sodium salt of E-benzaldehyde oxime in dimethyl sulfoxide in the presence of sodium hydride.
  • Example 2 shows the synthesis of trifluoromethyl substituted hydroxy- and dihydroxy- chlorins using (trifluoromethyl)trimethylsilane as nucleophilic agent.
  • Example 3 shows the synthesis of alkyl, alkenyl, alkynyl and aryl substituted hydroxy- and dihydroxy-chlorins using organometallic, more precisely Grignard reagents.
  • the specifically substituted amphiphilic chlorin derivatives produced according to the present invention are suitable to be used for photodynamic therapy of cancer and other (hyper) proliferative diseases and infections.
  • PDT is accomplished by first incorporating the derivatives into a
  • one of the main advantages is that convenient pharmaceutical formulations can be created for the biologically active compounds of the present invention such as liposomal formulation to be injected avoiding
  • amphiphilic compounds are formulated into liposomes. This liposomal formulation can then be injected avoiding undesirable effects such as precipitation at the injection site or delayed pharmacokinetics of the tetrapyrrole systems.
  • the disclosed porphyrin and chlorin derivatives in the diagnosis and treatment of arthritis and similar inflammatory diseases
  • the data presented in examples 6.1, 6.2 and 6.3 show the remarkable results of the photodynamic treatment of two cell lines especially relevant for arthritis (HIG82 and J774A.1, a rabbit synoviocyte and a mouse macrophage cell line) with three compounds of the present invention.
  • Tetrahexylporphyrin, tetraphenylporphynn and tetrakis-(3-methoxyphenyl)-porphyrin were prepared using Lindsey's conditions (J. S. Lindsey, I. C. Schreiman, H. C. Hsu, P. C. Kearney and A. M. Marguerettaz, J. Org. Chem. 1987, 52, 827-836).
  • Dichloromethane was purified by distillation over K 2 C0 3 prior to use. Thin layer chromatography (TLC) was performed using Merck silica gel 60 (without
  • dichloromethane (1.6 g, 1.8 mmol) was added drop wise to a stirred solution of 5, 10, 15,20-tetrahexyl-7-dmydro-8-oxo-7,8-chlorm (250 mg, 0.37 mmol) in dichloromethane (15 ml), until the starting material was consumed. Then water (50 ml) was added, the organic layer was separated, washed with water (50 ml), dried over anhydrous sodium sulfate and the solvent was removed.
  • osmium tetroxide 1000 mg, 3.9 mmol was added to a stirred solution of 5 J 10,15,20-tetrakis-(3-methoxyphenyl)-porphyrin (2500 mg, 3.4 mmol) in dichloromethane/pyridine 1 :1 (340 ml). After stirring for 4 days, a saturated solution of sodium bisulfite in water/methanol 1 :1 (150 ml) was added and the mixture was stirred for 18 h. The reaction mixture was filtered through Celite and dried over anhydrous sodium sulfate.
  • the solvent was evaporated and the residue was purified by flash chromatography with dichloromethane/ethyl acetate 9: 1 as eluent, followed by recrystallization from dichloromethane/aqueous methanol.
  • the first band from the column contained starting material (793 mg, 32 %) and the second band the title compound 5,10,15,20-tetrakis-(3-methoxyphenyl)-7,8-dihydroxy-7,8-chlorin (954 mg, 36 %).
  • dichloromethane (1 g, 1.1 mmol) was added drop wise within 2 h to a stirred solution of 5,10,15,20-tetrakis-(3-methoxyphenyl)-7-dihydro-8-oxo-7,8-chlorin (160 mg, 0.21 mmol) in dichloromethane (20 ml) and stirred for further 3 h. Then water (50 ml) was added, the organic layer was separated, washed with water (50 ml), dried over anhydrous sodium sulfate and the solvent was removed.
  • the photosensitizing activity was determined in the human colon adenocarcinoma cell line HT29.
  • the HT29 cell lines were grown in DMEM (cc- pro GmbH) supplemented with 10 % heat-inactivated fetal calf serum (FCS, cc- pro GmbH), 1 % penicillin (10000 IU) and streptomycin (10000 //g/ml, cc-pro GmbH).
  • FCS heat-inactivated fetal calf serum
  • streptomycin 10000 //g/ml, cc-pro GmbH.
  • Cells were kept as a monolayer culture in a humidified incubator (5 % C0 2 in air at 37 °C).
  • a photosensitizer stock solution (2 mM) was performed in DMSO and was kept in the dark at 4 °C. Further dilution was performed in RPMI 1640 medium, without phenol red supplemented with 10 % FCS to reach a final photosensitizer concentration of 2 or 10
  • the cell viability was assessed by the XTT assay.
  • 500 mg XTT sodium 3 '- [phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid, Applichem GmbH
  • 500 ml PBS-buffer without Ca and Mg 2
  • PMS N-methyl dibenzopyrazine methyl sulfate, Applichem GmbH
  • the solution should be stored frozen and should not be exposed to light.
  • the XTT reagent solution was thawed in a 37 °C water bath and the activation solution (PMS) was added immediately prior to use.
  • PMS activation solution
  • the medium in the micro plate was exchanged with fresh RPMI without phenol red and 10 % FCS (100 ⁇ ) prior adding 50 ⁇ XTT reaction solution per well.
  • the micro plate was incubated for 2-3 hours at 37 °C and 5 % C0 until an orange dye is to be formed. The micro plate has been shaken gently to evenly distribute the dye in the wells.
  • mice monocytes-macrophages cell line J774A.1 and the rabbit synoviocyte cell line HIG-82 were grown in DMEM (cc-pro GmbH) supplemented with 10 % heat-inactivated fetal calf serum (FCS, cc-pro GmbH), 1 % penicillin (10000 IU) and streptomycin (10 000 g/ml, cc-pro GmbH). Cells were kept as a monolayer culture in a humidified incubator (5 % C0 2 in air at 37 °C).
  • a photosensitizer stock solution (2 mM) was performed in DMSO and was kept in the dark at 4 °C. Further dilution was performed in RPMI 1640 medium without phenol red supplemented with 10 % FCS, to reach a final photosensitizer concentration of 2 or 10 ⁇ , respectively.
  • the cell viability was assessed by the XTT assay.
  • 500 mg XTT sodium 3'- [phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid, Applichem GmbH
  • 500 ml PBS-buffer without Ca + and Mg 2
  • PMS N-methyl dibenzopyrazine methyl sulfate, Applichem GmbH
  • the solution was stored frozen and was not exposed to light.
  • the XTT reagent solution was thawed in a 37 °C water bath and the activation solution (PMS) was added immediately prior to use.
  • PMS activation solution
  • the medium in the micro plate was exchanged with fresh RPMI without phenol red and 10 % FCS (100 ⁇ ), prior adding 50 ⁇ XTT reaction solution per well.
  • the micro plate was incubated for 2- 3 hours at 37 °C and 5 % C0 2 until an orange dye was formed. The micro plate was shaken gently to evenly distribute the dye in the wells.
  • the absorbance of the samples was measured with a spectrophotometer (Bio- Kinetics Reader EL312 e; Bio-Tek Instruments Inc.) at a wavelength of 490 run.
  • a spectrophotometer Bio- Kinetics Reader EL312 e; Bio-Tek Instruments Inc.
  • reference absorbance to measure non-specific readings
  • a wavelength of 630-690 nm was used.
  • FIG. 12 to 14 illustrate the photodynamic activity of selected
  • photosensitizers against synoviocytes and macrophages, cell types which are especially relevant for the treatment of arthritis and similar inflammatory diseases are especially relevant for the treatment of arthritis and similar inflammatory diseases.

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  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne des procédés permettant d'obtenir des composés biologiquement actifs qui peuvent être utilisés en tant que photosensibilisants pour des applications diagnostiques et thérapeutiques. Lesdites applications sont en particulier la TPD du cancer, d'infections et d'autres maladies hyperprolifératives, le diagnostic de fluorescence, et la TPD d'une indication non tumorale, telle que l'arthrite, les maladies inflammatoires, les infections virales ou bactériennes, et les troubles dermatologiques, ophtalmologiques ou urologiques. Dans un mode de réalisation, la présente invention consiste en un procédé destiné à synthétiser des dicéto-chlores en tant que précurseurs. Dans un autre mode de réalisation, lesdits précurseurs sont convertis en chlores hydroxy et dihydroxy β-fonctionnalisés. Un autre mode de réalisation consiste à procurer des composés amphiphiles permettant une affinité membranaire supérieure et une efficacité accrue de la TPD. Un autre mode de réalisation consiste à formuler l'isomère désiré en une formulation liposomale devant être injectée, ce qui évite les effets indésirables tels que la précipitation sur le site d'injection ou une pharmacocinétique retardée des systèmes de tétrapyrrole.
PCT/US2011/047576 2010-07-22 2011-08-12 Application de chlores-dihydroxy β-fonctionnalisés pour tpd WO2012012809A2 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
PL11810524T PL2870159T3 (pl) 2010-07-22 2011-08-12 Zastosowanie β-funkcjonalizowanych dihydroksychloryn do PDT
EP11810524.6A EP2870159B1 (fr) 2010-07-22 2011-08-12 APPLICATION DE CHLORES-DIHYDROXY ß-FONCTIONNALISÉS POUR TPD
MX2013000877A MX353394B (es) 2010-07-22 2011-08-12 Aplicación de dihidroxiclorinas beta-funcionalizadas para tfd.
PCT/US2011/047576 WO2012012809A2 (fr) 2010-07-22 2011-08-12 Application de chlores-dihydroxy β-fonctionnalisés pour tpd
JP2013520904A JP2013532664A (ja) 2010-07-22 2011-08-12 ＰＤＴのためのβ−官能化ジヒドロキシ−クロリンの用途
BR112013001576A BR112013001576A2 (pt) 2010-07-22 2011-08-12 composto tetrapirrólico e composição farmacêutica derivado farmacêuticamente aceitável da mesma e respectivos usos e métodos de terapia fotodinâmica e de diagnóstico e tratamento da artrite e de doenças inflamatórias semelhantes.
CN201180039522.7A CN103097390B (zh) 2010-07-22 2011-08-12 β‑官能化二羟基‑二氢卟酚用于PDT的应用
IL224381A IL224381B (en) 2010-07-22 2013-01-23 Application of b-functionalized dihydroxy-chlorins for pdt

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US36670710P 2010-07-22 2010-07-22
US61/366,707 2010-07-22
PCT/US2011/047576 WO2012012809A2 (fr) 2010-07-22 2011-08-12 Application de chlores-dihydroxy β-fonctionnalisés pour tpd

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WO2012012809A2 true WO2012012809A2 (fr) 2012-01-26
WO2012012809A3 WO2012012809A3 (fr) 2012-05-18

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EP (1) EP2870159B1 (fr)
JP (1) JP2013532664A (fr)
CN (1) CN103097390B (fr)
BR (1) BR112013001576A2 (fr)
IL (1) IL224381B (fr)
MX (1) MX353394B (fr)
PL (1) PL2870159T3 (fr)
WO (1) WO2012012809A2 (fr)

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WO2013015774A1 (fr) 2011-07-22 2013-01-31 Biolitec Pharma Marketing Ltd Dihydroxy-chlorines glyco-substituées et chlorines bêta-fonctionnalisées pour thérapie antimicrobienne photodynamique
EP2616065A1 (fr) * 2010-07-22 2013-07-24 Biolitec Pharma Marketing Ltd Dihydroxy-chlorines glyco-substituées et chlorines bêta-fonctionnalisées pour thérapie antimicrobienne photodynamique
US9722103B2 (en) 2015-06-26 2017-08-01 Sunpower Corporation Thermal compression bonding approaches for foil-based metallization of solar cells

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CN103995045A (zh) * 2014-05-29 2014-08-20 武汉矽感科技有限公司 离子迁移谱仪用于检测乐果和马拉硫磷残留的用途及方法
CN104940950B (zh) * 2015-07-09 2017-11-28 武汉大学 一种肿瘤靶向多肽光敏剂键合物
CN111196819B (zh) * 2018-11-16 2023-03-28 中国科学院上海药物研究所 一类d-a-d型苯并吡嗪类化合物及制备方法和应用

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US9315510B2 (en) * 2008-09-18 2016-04-19 Biolitec Pharma Marketing Ltd Method and application of unsymmetrically meso-substituted porphyrins and chlorins for PDT
JP6041360B2 (ja) * 2011-07-22 2016-12-07 バイオリテック ウンターネーメンスベタイリグンクス ツヴァイ アクツィエンゲゼルシャフト 抗菌性光線力学療法のための、糖−置換ジヒドロキシ−クロリン及びβ−官能化クロリン

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See also references of EP2870159A4

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2616065A1 (fr) * 2010-07-22 2013-07-24 Biolitec Pharma Marketing Ltd Dihydroxy-chlorines glyco-substituées et chlorines bêta-fonctionnalisées pour thérapie antimicrobienne photodynamique
EP2616065A4 (fr) * 2010-07-22 2014-05-14 Biolitec Pharma Marketing Ltd Dihydroxy-chlorines glyco-substituées et chlorines bêta-fonctionnalisées pour thérapie antimicrobienne photodynamique
WO2013015774A1 (fr) 2011-07-22 2013-01-31 Biolitec Pharma Marketing Ltd Dihydroxy-chlorines glyco-substituées et chlorines bêta-fonctionnalisées pour thérapie antimicrobienne photodynamique
US9722103B2 (en) 2015-06-26 2017-08-01 Sunpower Corporation Thermal compression bonding approaches for foil-based metallization of solar cells

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CN103097390A (zh) 2013-05-08
BR112013001576A2 (pt) 2016-07-19
EP2870159B1 (fr) 2017-06-28
PL2870159T3 (pl) 2018-01-31
IL224381B (en) 2018-03-29
EP2870159A2 (fr) 2015-05-13
CN103097390B (zh) 2017-03-08
JP2013532664A (ja) 2013-08-19
MX353394B (es) 2018-01-11
WO2012012809A3 (fr) 2012-05-18
MX2013000877A (es) 2013-07-03
EP2870159A4 (fr) 2015-08-12

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